It has become apparent that conditioning of drug effects to cues associated with cocaine and other psychomotor stimulants plays a very critical role in the development and maintenance of drug-induced sensitization, as well as the addictive processes related to these pharmacological agents. One aim of this research program was to define further the neuropharmacological and neuroanatomical substrates underlying those conditioned effects and to characterize the behavioral variables involved in their acquisition, retention, and extinction. In addition to its euphorogenic actions, cocaine also has anxiogenic properties. We have found that environmental cues associated with cocaine can elicit long-lasting anxiogenic-like actions that are reversed by pretreatment with the CRF antagonist alpha-helical-CRF. Cocaine-associated cues were also found to elicit conditioned release of plasma corticosterone, suggestion that some of the conditioned effects of cocaine involve activation of the H-P-A axis. We have also found that pretreatment of rats with eticlopride (a D2 dopamine antagonist) prior to a series of extinction sessions prevented the expression of cocaine- conditioned behaviors, but had no effect on the extinction process. Neither the D1 antagonist SCH 23310 nor apomorphine had an appreciable effect on extinction. Lesions of the frontal cortex failed to alter either expression of cocaine-conditioned increases in locomoter activity or the extinction of such behavior. Conditioned increases in locomotor activity were also established to discrete auditory, visual, and olfactory cues associated with intravenous injections of cocaine. Surprisingly, such conditioned effects were rather labile and subject to rapid extinction. Cues associated with cocaine were also found to increase glucose utilization in the medial frontal cortex, basolateral amygdala, core and shell of the n. accumbens, VTA and various midline thalamic nuclei. Increased metabolic activity in these structures appear to be related to the expression of conditioned cocaine effects and may underlie the incentive motivational processes responsible for craving.